Sensor Chip for Monitoring Tumors

ScienceDaily (Aug. 29, 2011) — A chip implant may soon be capable of monitoring tumors that are difficult to operate on or growing slowly. Medical engineers at Technische Universitaet Muenchen (TUM) have developed an electronic sensor chip that can determine the oxygen content in a patient's tissue fluid. This data can then be wirelessly transmitted to the patient's doctor to support the choice of therapy. A drop in oxygen content in tissue surrounding a tumor indicates that the tumor might be growing faster and becoming aggressive.

Sensor chip (held between two fingers) for measuring the concentration of dissolved oxygen in tissue; the biocompatible housing (open) also contains a transmitter, analysis unit and a battery. 

Surgery is usually one of the first therapy options in cancer treatment. However, some tumors, such as brain tumors, can be difficult to operate on if there is a risk of damaging surrounding nerve tissue. Other cancerous tumors, such as prostate carcinoma, grow at a very slow rate and primarily affect older patients. Operating in these cases often lowers patients' quality of life without significantly extending their life expectancy.

A team of medical engineers headed by Prof. Bernhard Wolf at the TUM Heinz Nixdorf Chair of Medical Electronics have now developed a sensor chip that can be implanted close to a tumor. The sensor chip measures the concentration of dissolved oxygen in the tissue and wirelessly transmits this information to a receiver carried by the patient. The receiver forwards the data to the patient's doctor, who can then monitor the tumor's development and arrange for an operation or therapies such as chemotherapy. The tumor is thus continually monitored and the patient does not have to visit the practice or hospital as frequently for check-ups.

The sensor chip has already passed laboratory tests with cell and tissue cultures. The main challenge for the researchers was developing a sensor that functions entirely autonomously for long periods of time. The sensor must continue to function and deliver correct values even in the presence of protein contamination or cell debris. It also has to be "invisible" to the body so that it is not identified as a foreign object, attacked and encapsulated in tissue.

"We designed the sensor chip to self-calibrate to a set dissolved oxygen concentration at measurement intervals," explains engineer and project manager Sven Becker. "In addition, we enclosed the sensor chip, analysis electronics, transmitter and batteries in a biocompatible plastic housing."

Not even twice the size of a thumbnail, the sensor chip and electronics have a compact footprint. However, the package must be made even smaller before it can be implanted in cancer patients using minimally invasive surgery. In addition, the designers want to add additional sensors for measuring acidity and temperature. Also at the development phase is a miniature medication pump to be implanted with the sensor chip. The pump will be able to release chemotherapeutic agents in direct proximity to the tumor if necessary. Before moving on to the next phase, the sensor has to pass trials in

animals. The researchers hope that the new technology will make cancer therapies more targeted and less aggressive for patients.

The IntelliTuM (Intelligent Implant for Tumor Monitoring) project was supported by the Heinz Nixdorf Stiftung and received EUR 500,000 in funding from Germany's Federal Ministry of Education and Research.

New Imaging Method Sheds Light On Cell Growth

ScienceDaily (Aug. 29, 2011) — University of Illinois researchers are giving a light answer to the heavy question of cell growth.

Illinois researchers developed a novel imaging technique, spatial light interference microscopy (SLIM), that can quantitatively measure cell mass with light.

Led by electrical and computer engineering professor Gabriel Popescu, the research team developed a new imaging method called spatial light interference microscopy (SLIM) that can measure cell mass using two beams of light. Described in the Proceedings of the National Academy of Sciences, the SLIM technique offers new insight into the much-debated problem of whether cells grow at a constant rate or exponentially.

SLIM is extremely sensitive, quantitatively measuring mass with femtogram accuracy. By comparison, a micron-sized droplet of water weighs 1,000 femtograms. It can measure the growth of a single cell, and even mass transport within the cell. Yet, the technique is broadly applicable.

"A significant advantage over existing methods is that we can measure all types of cells -- bacteria, mammalian cells, adherent cells, nonadherent cells, single cells and populations," said Mustafa Mir, a graduate student and a first author of the paper. "And all this while maintaining the sensitivity and the quantitative information that we get."

Unlike most other cell-imaging techniques, SLIM -- a combination of phase-contrast microscopy and holography -- does not need staining or any other special preparation. Because it is completely non-invasive, the researchers can study cells as they go about their natural functions. It uses white light and can be combined with more traditional microscopy techniques, such as fluorescence, to monitor cells as they grow.

"We were able to combine more traditional methods with our method because this is just an add-on module to a commercial microscope," Mir said. "Biologists can use all their old tricks and just add our module on top."

Because of SLIM's sensitivity, the researchers could monitor cells' growth through different phases of the cell cycle. They found that mammalian cells show clear exponential growth only during the G2 phase of the cell cycle, after the DNA replicates and before the cell divides. This information has great implications not only for basic biology, but also for diagnostics, drug development and tissue engineering.

The researchers hope to apply their new knowledge of cell growth to different disease models. For example, they plan to use SLIM to see how growth varies between normal cells and cancer cells, and the effects of treatments on the growth rate.

Popescu, a member of the Beckman Institute for Advanced Science and Technology at the U. of I., is establishing SLIM as a shared resource on the Illinois campus, hoping to harness its flexibility for basic and clinical research in a number of areas.

"It could be used in many applications in both life sciences and materials science," said Popescu, who also is a professor of physics and of bioengineering. "The interferometric information can translate to the topography of silicon wafers or semiconductors. It's like an iPad -- we have the hardware, and there are a number of different applications dedicated to specific problems of interest to different labs."

Co-authors on the paper include graduate students Zhuo Wang, Zhen Shen and Michael Bednarz, along with electrical and computer engineering professor Rashid Bashir, physics professor Ido Golding and cell and developmental biology professor Supriya G. Prasanth.

The National Science Foundation and the Grainger Foundation supported this work.

Statins Reduce Deaths from Infection and Respiratory Illness, Data Eight Years On from Trial Suggests

ScienceDaily (Aug. 29, 2011) — The death rate among patients prescribed a statin in a major trial that ended in 2003 is still lower than those given a placebo, even though most participants in both groups have been taking statins ever since. ASCOT, the Anglo-Scandinavian Cardiac Outcomes Trial, was stopped early because the statin was so effective at preventing heart attacks and strokes, but a new analysis has shown that eight years on, the most significant difference between the groups is a reduction in deaths from infection and respiratory illness.

The latest findings, from researchers at Imperial College London, were presented at the European Society of Cardiology Congress in Paris August 28 and simultaneously published in the European Heart Journal.

In the lipid-lowering arm of the trial, over 10,000 patients in the UK, Ireland and Scandinavia with high blood pressure were randomly allocated either atorvastatin or placebo between 1998 and 2000. In 2003, the trial was stopped early because the statin proved to be highly beneficial in preventing heart attacks and strokes. Since then, most participants from both groups have been taking statins.

The new analysis looked at the number and cause of deaths among the 4,605 participants in the ASCOT trial who are based in the UK. After 11 years' follow-up, overall mortality is 14 per cent lower in the group originally assigned atorvastatin, due largely to fewer deaths from infection and respiratory illness.

"This result is very unexpected," said Professor Peter Sever, from the International Centre for Circulatory Health at Imperial College London, who led the study. "The benefits of statins for preventing heart attacks and strokes are well-established, but after long-term follow-up the most significant effects seem to be on deaths from other causes. It's quite remarkable that there is still this difference between the two groups, eight years after the trial finished.

"Some studies have suggested that statins protect people against death from infectious diseases such as pneumonia. More research is needed to explain how these drugs might have unforeseen actions that prevent deaths from other illnesses."

Amongst UK participants, in the 11 years since the trial began, 460 of the original statin group have died, compared with 520 of the placebo group. The difference is largely explained by a 36 per cent reduction in deaths from infection and respiratory illness. Deaths from cardiovascular disease were also lower in the original statin group, but the difference was not statistically significant. There was no difference in deaths from cancer.

The initial results of the ASCOT lipid arm had a major influence on subsequent guidelines recommending the use of statins for people at risk of heart disease, including those produced by NICE in the UK. Another arm of the trial comparing different combinations of blood pressure-lowering drugs also had an important impact on clinical practice.

The study was investigator-led with funding provided by Pfizer. Professor Sever is a National Institute for Health Research (NIHR) Senior Investigator and he was supported by the Comprehensive Biomedical Research Centre award to Imperial College Healthcare NHS Trust, from the NIHR.

Genetic Variant Linked to Development of Liver Cancer in Hepatitis C Virus Carriers

ScienceDaily (Aug. 29, 2011) — A genome-wide study by researchers at the RIKEN Center for Genomic Medicine, Hiroshima University Hospital and Sapporo-Kosei General Hospital has identified a genetic variant associated with the development of liver cancer in chronic hepatitis C virus carriers. The findings are based on a study of 3,312 Japanese individuals and appear in the journal Nature Genetics.

Results of genome-wide association study (GWAS) on HCV-related HCC (977 subjects). Horizontal axis represents chromosome position, vertical axis represents P-values. An SNP with statistically significant association (P=1.07x10-7) was confirmed on chromosome 22 (region of DEPDC5 locus).

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the third leading cancer-related cause of death and the seventh most common form of cancer worldwide. The hepatitis C virus (HVC) is the main risk factor for HCC in many western countries and in Japan, where of the more than 30,000 deaths each year from HCC, 70% involve HVC.

To identify risk factors connecting HVC and HCC, the research group conducted a genome-wide study on a group of 3,312 Japanese individuals carrying the hepatitis C virus. Analyzing a total of 467,538 genetic markers (called single nucleotide polymorphisms or SNPs) in a group of 212 HCV carriers with HCC and 765 HCV carriers without HCC, the group uncovered one SNP associated with HCC risk, located on a gene called DEPDC5. The association was confirmed in an independent replication study on a population of 2335 HVC carriers, 710 with HCC and 1625 without HCC.

The significance of the findings was further highlighted when the researchers adjusted their results for gender, age and platelet count, revealing that among Japanese individuals with chronic HVC infection, the DEPDC5 SNP roughly doubles the odds of developing HCC.

While deepening our understanding of the mechanisms triggering HCC, the discovery of the DEPDC5 SNP locus also provides a valuable target for new therapy techniques, promising progress in the ongoing battle to overcome one of the world's most deadly cancers.

The Brittleness of Aging Bones: More Than Loss of Bone Mass

ScienceDaily (Aug. 29, 2011) — It is a well-established fact that as we grow older, our bones become more brittle and prone to fracturing. It is also well established that loss of mass is a major reason for older bones fracturing more readily than younger bones, hence medical treatments have focused on slowing down this loss. However, new research from scientists at the U.S. Department of Energy (DOE)'s Lawrence Berkeley National Laboratory (Berkeley Lab) shows that at microscopic dimensions, the age-related loss of bone quality can be every bit as important as the loss of quantity in the susceptibility of bone to fracturing.

At each size scale, the hierarchical structure of human cortical bone influences its susceptibility to fracturing with smaller levels affecting intrinsic toughness and higher levels impacting extrinsic toughness. 

Using a combination of x-ray and electron based analytical techniques as well as macroscopic fracture testing, the researchers showed that the advancement of age ushers in a degradation of the mechanical properties of human cortical bone over a range of different size scales. As a result, the bone's ability to resist fracture becomes increasingly compromised. This age-related loss of bone quality is independent of age-related bone mass loss.

"In characterizing age-related structural changes in human cortical bone at the micrometer and sub micrometer scales, we found that these changes degrade both the intrinsic and extrinsic toughness of bone," says Berkeley Lab materials scientist Robert Ritchie. "Based on multiscale structural and mechanical tests, we attribute this degradation to a hierarchical series of coupled mechanisms that start at the molecular level."

Ritchie, who holds joint appointments with Berkeley Lab's Materials Sciences Division and the University of California (UC) Berkeley's Materials Science and Engineering Department, is the senior author of a paper published in theProceedings of the National Academy of Science (PNAS) that describes this work. The paper is titled "Age-related changes in the plasticity and toughness of human cortical bone at multiple length scales."

Co-authoring the PNAS paper with Ritchie were Elizabeth Zimmermann, Eric Schaible, Hrishikesh Bale, Holly Barth, Simon Tang, Peter Reichert, Björn Busse, Tamara Alliston and Joel Ager.

Human cortical or compact bone is a composite of collagen molecules and nanocrystals of a mineralized form of calcium called hydroxyapatite (HA). Mechanical properties of stiffness, strength and toughness arise from both the characteristic structure at the nanoscale, and at multiple length scales through the hierarchical architecture of the bone. These length scales extend from the molecular level to the osteonal structures at near-millimeter levels. An osteon is the basic structural unit of compact bone, composed of a central canal surrounded by concentric rings of lamellae plates, through which bone remodels.

"Mechanisms that strengthen and toughen bone can be identified at most of these structural length scales and can be usefully classified, as in many materials, in terms of intrinsic toughening mechanisms at small length scales, promoting non-brittle behavior, and extrinsic toughening mechanisms at larger length scales acting to limit the growth of cracks," Ritchie says. "These features are present in healthy, young human bone and are responsible for its unique mechanical properties. However, with biological aging, the ability of these mechanisms to resist fracture deteriorates leading to a reduction in bone strength and fracture toughness."

Working with the exceptionally bright beams of x-rays at Berkeley Lab's Advanced Light Source (ALS), Ritchie and his colleagues analyzed bone samples that ranged in age between 34 and 99 years. In situ small-angle x-ray scattering and wide-angle x-ray diffraction were used to characterize the mechanical response of the collagen and mineral at the sub micrometer level. A combination of x-ray computed tomography and in situ fracture-toughness measurements with a scanning electron microscope were used to characterize effects at micrometer levels.

"We found that biological aging increases non-enzymatic cross-linking between the collagen molecules, which suppresses plasticity at nanoscale dimensions, meaning that collagen fibrils can no longer slide with respect to one another as a way to absorb energy from an impact," Ritchie says. "We also found that biological aging increases osteonal density, which limits the potency of crack-bridging mechanisms at micrometer scales."

These two mechanisms that act to reduce bone toughness are coupled, Ritchie says, in that the increased stiffness of the cross-linked collagen requires energy to be absorbed by "plastic" deformation at higher structural levels, which occurs by the process of micro cracking.

"With age, remodeling of the bone can lead the osteons to triple in number, which means the channels become more closely packed and less effective at deflecting the growth of cracks," he says. "This growing ineffectiveness must be accommodated at higher structural levels by increased micro cracking. In turn, the increased micro cracking compromises the formation of crack bridges, which provide one of the main sources of extrinsic toughening in bone at length scales in the range of tens to hundreds of micrometers. Thus, age-related changes occur across many levels of the structure to increase the risk of fracture with age."

This research was supported by a grant from the the National Institutes of Health. The Advanced Light Source is a national user facility supported by the DOE Office of Science.